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cis-Determinants in the cytoplasmic domain of CEACAM1 responsible for its tumor inhibitory function

Oncogene volume 18, pages 5563–5572 (1999)Cite this article

Abstract

CEACAM1, also known as C-CAM, BGP and CD66a, is a member of the carcinoembryonic antigen (CEA) family which is itself part of the immunoglobulin supergene family. CEACAM1 is involved in intercellular adhesion, signal transduction and tumor cell growth regulation. CEACAM1 is down-regulated in colon and prostate carcinomas, as well as in endometrial, bladder and hepatic tumors, and 30% of breast cancers. We have shown in a mouse colon tumor model that CEACAM1 with a long cytoplasmic domain inhibited the development of tumors whereas a splice variant lacking the cytoplasmic domain did not. In this study, we define the subregions of the long cytoplasmic domain participating in the tumor inhibition phenotype of CEACAM1. We show that a single point mutation of Tyr488, conforming to an Immunoreceptor Tyrosine Inhibition Motif (ITIM), was sufficient to reverse the in vivo tumor cell growth inhibition. Substitution or deletion of residues in the C-terminal region of the CEACAM1 cytoplasmic domain also led to reversal of tumor cell growth inhibition. This result is in agreement with our previous studies demonstrating the C-terminal region of the cytoplasmic domain influences the levels of CEACAM1 Tyr phosphorylation and its association with the protein Tyr phosphatases SHP-1 and SHP-2. Furthermore, removal of the N-terminal domain of CEACAM1, essential for intercellular adhesion, did not impair the tumor inhibitory effect. These results suggest that Tyr phosphorylation or dephosphorylation of the CEACAM1 cytoplasmic domain represents a crucial step in the control of epithelial cell proliferation.

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Acknowledgements

The authors are greatly indebted to Dr Gabriela Dveksler (US University of the Health Sciences, Bethesda, MD, USA) for providing the CEACAM1/Δ4-122 mutants and Dr Kathryn V Holmes (University of Colorado, Denver, CO, USA) for the 655 serum and Dr Michael Brattain (University of Toledo, Toledo, OH, USA) for providing the mouse CT51 cells. These studies were funded by the Cancer Research Society Inc. L Izzi and T Kunath are supported by studentships from the Medical Research Council of Canada. C Houde and N Beauchemin are respectively funded by a studentship and a Senior Scholarship from the Fonds de la Recherche en Santé du Québec.

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  1. Department of Biochemistry, McGill Cancer Centre, McIntyre Medical Sciences Building, Room 716, McGill University, 3655 Drummond Street, Montreal, Québec, Canada

    Luisa Izzi, Claire Turbide, Caroline Houde & Nicole Beauchemin

  2. Department of Medicine and Oncology, McGill Cancer Centre, McIntyre Medical Sciences Building, Room 716, McGill University, 3655 Drummond Street, Montreal, Québec, Canada

    Nicole Beauchemin

  3. The Samuel Lunenfeld Research Institute, Toronto, Canada

    Tilo Kunath

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  1. Luisa Izzi
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Izzi, L., Turbide, C., Houde, C. et al. cis-Determinants in the cytoplasmic domain of CEACAM1 responsible for its tumor inhibitory function. Oncogene 18, 5563–5572 (1999). https://doi.org/10.1038/sj.onc.1202935

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